Natural killer (NK) cells are lymphocytes, which arise from a common lymphoid progenitor cell during hematopoiesis. Unlike T and B lymphocytes, however, NK cells do not express rearranged antigen receptors and are therefore considered part of the innate immune system. NK cells have the unique ability to kill tumor or virally-infected cells without prior immunization. Another major function of NK cells is to secrete cytokines, such as IFN-γ and TNF-α, which augment inflammatory immune responses and also influence adaptive immunity.
Human NK cells are defined as CD56+CD3− lymphocytes, which morphologically are indistinguishable from CD8+ granular T cells. The circulating pool of NK cells in humans consists of two populations: CD56dimCD16bright and CD56brightCD16dim. The former population is predominant (>95% of circulating NK cells), has more cytotoxic than cytokine-producing activity, and may represent a mature NK cell population which evolves from CD56brightCD16dim cells (Cooper et al. Trends Immunol 2001; 22:633-640). Accordingly, CD56bright NK cells express CD117, higher levels of CD94 (which heterodimerizes with NKG2A (Natural Killer Group 2, member A) or NKG2C to form HLA-E recognition receptors), and CCR7, which may allow for NK cell trafficking to lymph nodes (Campbell et al. J. Immunol 2001; 166).
In contrast, CD56dim NK cells express higher levels of killer immunoglobulinlike receptors (KIRs) and the natural cytotoxicity receptors (NCRs), which include NKp30, NKp44, and NKp46, important for tumor cell recognition and lysis. CD56dim NK cells down-regulate expression of CCR7 and express CXCR1, which binds IL-8 and is postulated to aid in the CD56dim NK cell response to inflammation (Campbell et al. 2001). Members of the KIR family are critical for transmission of inhibitory signals to NK cells upon binding of self-MHC class I molecules, thus mediating self-tolerance of CD56dim NK cells. Expression of CD16, also known as the low-affinity IgG Fc receptor, also allows CD56dim NK cells to mediate antibody-dependent cell-mediated cytotoxicity in the presence of antibody specific to target cells. Both types of NK cells express NKG2D, a homodimeric activating receptor, which binds stress-inducible ligands on tumor cells.
It has been traditionally postulated that human NK cells develop in the bone marrow, but recent data suggest that NK cell precursors from the bone marrow may migrate to secondary lymphoid organs, where maturation of NK precursors into CD56bright NK cells can occur. The NK cell precursors identified in lymph nodes have been divided into subsets based on expression of CD34, CD94, and CD117 (Freud et al. Immunol Rev 2006; 214:56-72). In line with this hypothesis, CD56bright NK cells are found preferentially in lymph nodes and can express CD16, KIRs, and NCRs, as well as acquire cytotoxic activity, upon activation (Fehniger T A et al. Blood 2003; 101:3052-3057; Ferlazzo G, et al. J Immunol 2004; 172:1455-1462.
In vitro, both mouse and human NK cells can differentiate from bone marrow- or cord blood-derived hematopoietic progenitor cells (HPCs) in the presence of cytokines alone; these NK cells appear phenotypically immature and resemble CD56bright cells (Colucci et al. Nat Rev Immunol 2003; 3:413-425). Culture of HPCs in the presence of both cytokines and stromal cells allows for further maturation of NK cells, including acquisition of KIRs or the murine equivalent, the Ly49 receptor family (Cooley et al. Blood 2007; 110:578-586; Williams et al. J Immunol 1999; 163:2648-2656).